1. Field of the Invention
The invention relates to a method for the preparation of a composition of nanoparticles, called metal oxide nanocrystals, of at least one metal oxide in the crystalline state, from at least one organometallic precursor in an aprotic solvent medium and in the presence of at least one ligand chosen from the group of organic compounds which have at least one carbon chain and are soluble in said aprotic solvent medium. It also relates to a composition of nanoparticles, called metal oxide nanocrystals, obtained in this way.
2. Description of the Related Art
Throughout the text, the following terminology is adopted:                nanoparticle: any particle of whatever shape having at least a width and thickness which are both less than 100 nm, typically of between 1 nm and 20 nm;        metal oxide nanocrystals: nanoparticles made up of at least one compound chosen from metal oxides in the crystalline state, each nanoparticle having the structure of the metal oxide(s), that is to say being formed from atoms of metal(s) and oxygen bonded to one another as in bulk metal oxides;        organometallic precursor: any coordination molecule or compound containing at least one organic group bonded to at least one metal atom (transition metal or compound of the main groups, that is to say, in particular, zinc, cadmium, boron, aluminum, gallium, indium, thallium, germanium, tin, titanium, zirconium, hafnium, the lanthanides (Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), scandium, yttrium, silicon, bismuth and the other transition metals) by a carbon atom or a hetero atom (chosen in particular from N, P, As, Si, S, Se, Te) of this organic group;        organometallic precursor which is spontaneously reactive to oxidation: organometallic precursor which is converted in an exothermic manner into an oxide in which the metal atom has a degree of oxidation greater than or equal to 1 when placed in the presence of at least one oxidizing agent (such as water, oxygen, ambient air . . . );        oxidizing agent: any agent allowing the conversion of an organometallic precursor into an oxide;        carbon chain: any aliphatic chain, saturated or unsaturated, straight or branched, substituted or unsubstituted, which may contain hetero atoms;        aprotic solvent medium: any composition which is not protogenic, does not have a hydrogen atom capable of forming hydrogen bonds, and in which water which may be present in traces does not act as a solvent agent; such a composition is capable of forming a liquid solution when brought into contact with at least one compound such as an organometallic precursor; it can be in the initially liquid state or, on the other hand, can pass into the liquid state only after contact with the compound(s) to be solubilized; it can be simple, that is to say formed by a single compound, or on the other hand complex and comprise several compounds; in particular, it can comprise not only one or more compound(s) which act as the solvent agent, but also any other compound which is not consumed by the formation reaction of metal nanocrystals—in particular in an oxidation reaction—is substantially neutral with respect to the dissolution of the organometallic precursor(s), and possibly plays a role in the formation reaction of metal nanocrystals—in particular in an oxidation reaction; such an aprotic solvent medium is, in particular, non-aqueous;        colloidal solution: any clear liquid composition of solid nanoparticles dispersed in a liquid; a liquid colloidal solution has several but not all of the properties of a true liquid solution, the nanoparticles remaining in the solid state; colloidal suspension or dispersion is also sometimes referred to;        water-compatible composition of nanoparticles: any composition of nanoparticles which can be dispersed at least in an aqueous medium, in particular any composition which can form a colloidal solution (liquid dispersion) in an aqueous medium;        organocompatible composition of nanoparticles: any composition of nanoparticles which can be dispersed in at least an organic—in particular non-aqueous—protic or aprotic medium, in particular any composition which can form a colloidal solution (liquid dispersion) with at least such an organic—in particular non-aqueous—protic or aprotic liquid medium;        coordinating group: any chemical group which can form a covalent, dative, hydrogen or electrostatic bond with metal atoms, metal ions, oxygen and metal oxides.        
WO 2004/092069 describes a method for the preparation of nanoparticles of at least one crystalline metal oxide, in which at least one organometallic precursor which is spontaneously reactive to oxidation is chosen, a liquid solution of each organometallic precursor in a non-aqueous solvent medium in the presence of at least one ligand which is soluble in said solvent medium is prepared, and this liquid solution is brought into contact with at least one oxidizing agent under reaction condition suitable for resulting directly in the production of metal oxide nanocrystals.
This method is satisfactory and enables the shape and size of the nanoparticles and their properties to be controlled. In addition, the thesis of Carole Pagès, University of Toulouse III-Paul Sabatier UFRPCA Laboratory of Coordination Chemistry, Dec. 17, 2007 pages 120 to 149 demonstrates in particular that the ligands which must be used for the preparation of such nanoparticles must necessarily have an aliphatic alkyl chain. Thus, it was not possible to obtain any composition of metal oxide nanocrystals by such a method in simple solution in an aprotic solvent medium in the presence of a ligand which does not have such an aliphatic alkyl chain.
This known method can be applied to any metal compound for which there is an organometallic precursor which is spontaneously reactive to oxidation and which can be solubilized in an aprotic solvent medium, or to any combination of such metal compounds. Among these metal compounds, there may thus be mentioned: zinc, cadmium, boron, aluminum, gallium, indium, thallium, germanium, tin, titanium, zirconium, hafnium, the lanthanides (Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu), scandium, yttrium, silicon, bismuth and the other transition metals.
All these known methods for the synthesis of metal oxide nanocrystals from organometallic precursors in an aprotic solvent medium have the disadvantage of producing compositions of nanocrystals of metal oxides which are organocompatible, but which on the other hand are not water-compatible.
In this respect, it is to be noted that although the presence of traces of water in the solvent medium are known to be able to play a role in the context of the oxidation reaction (cf. “Size- and Shape-Control of Crystalline Zinc Oxide Nanoparticles: A New Organometallic Synthetic Method”, Myrtil L. Kahn et al., Adv. Func. Mater. 2005, 15, no. 3, March), the presence of a significant and uncontrolled amount of water is strictly incompatible with the control of an organometallic decomposition reaction. Indeed, in the organometallic technical field, water is systematically considered to be detrimental, and even dangerous. More particularly, in the case of an oxidation reaction starting from an organometallic precursor, it is considered that the presence of a significant and uncontrolled amount of water in the medium would necessarily have the consequence at the very least of considerably disturbing and even preventing the functioning of the reaction. Indeed, it is known that any uncontrolled presence of water unavoidably leads to the formation of metal hydroxides (destructive and exothermic decompositions of the Zerewitinoff type) and is destructive and detrimental in the context of the preparation and use of organometallic compounds. Needless to say, reactions in the presence of organometallics are most often carried out in the presence of a water trap in order to work in a dry atmosphere.
This is all the more true in the case of an oxidation reaction such as is mentioned in WO2004/092069, in which a significant and uncontrolled amount of water would additionally necessarily lead to a disturbance in the functioning of the oxidation reaction itself. It is thus out of the question to carry out this type of reaction in the presence of an uncontrolled amount of water, or even in the presence of a hydrophilic compound which is capable of introducing a significant and uncontrolled amount of water into the reaction medium.
It would therefore be useful to enable such compositions of metal oxide nanocrystals which are water-compatible, and more particularly both organocompatible and water-compatible, that is to say which can be dispersed both, and as required, in aprotic—in particular organic non-aqueous—media and in protic media—in particular water and aqueous media—to be obtained. In particular it is important to obtain such water-compatible compositions to enable them to be used in numerous applications, in particular in physiological media, for therapeutic use or for medical imaging, and in all applications for which the aim is to avoid the use of organic solvents which are toxic and/or polluting volatile organic compounds (VOC), the use of which must be limited and even suppressed taking account environmental awareness regulations.
Various methods have already been proposed to enable compositions of nanocrystals of metal oxides which are initially not water-compatible to be rendered water-compatible.
A first approach could consist of exchanging the hydrophobic ligands for ligands which are analogous but have hydrophilic groups, such as polymers derived from PEG (thiol-PEG, amino-PEG, carboxy-PEG). However, this approach would necessitate a relatively complex second stage, the yield of which is not very good. In addition, it would not result in metal oxide nanocrystals doped exclusively with hydrophilic ligands, the exchange reaction never being total.
A second approach consists of incorporating into the composition obtained amphiphilic ligands which are capable of interacting with the hydrophobic ligands resulting from the preparation of the nanoparticles, without replacing these hydrophobic ligands, forming bilayer structures around the nanoparticles. The compositions obtained with this approach may have a certain toxicity (due to the release of amphiphilic compounds) and a poorly controlled stability, which is a disadvantage in particular in biological and therapeutic applications.
In certain very specific cases, another approach can consist of choosing, for carrying out the preparation of the nanoparticles, a ligand having, at one of the ends of the aliphatic alkyl chain a group which subsequently enables chemical reactions for grafting of a hydrophilic group to be carried out. But, there again, an additional stage is necessary, and this approach is only possible in very particular cases which are of little use in practice.
In addition, these various approaches also most often have the disadvantage that the compositions of nanoparticles which have been modified to be water-compatible subsequently are no longer organocompatible under satisfactory conditions.